Is EMC3 p.Arg93Trp (c.277C>T) pathogenic?

EMC3 p.Arg93Trp (c.277C>T) is classified Uncertain significance in EMC3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-21). AlphaMissense: likely pathogenic (0.9589); Very rare (popmax 0.00441%, sas).

How common is EMC3 p.Arg93Trp (c.277C>T) in the general population?

EMC3 p.Arg93Trp (c.277C>T) is very rare (popmax 0.00441%, sas) (gnomAD).

What do computational predictors say about EMC3 p.Arg93Trp (c.277C>T)?

AlphaMissense predicts likely pathogenic (score 0.9589) — an in-silico prediction, not a clinical call.

EMC3 p.Arg93Trp

c.277C>T · VCV4017720

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9589 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00441%, sas)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.9589	likely pathogenic
REVEL	0.357	indeterminate
SaProt	LLR -9.64	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.9	GERP -0.31, phastCons 1
Regional constraint	o/e 0.73	unconstrained · MANE · 13 kb · p 0.00032 · regional, not allelic
Overall
CADD	24.3	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00441% South Asian · 4/90,670 alleles

Filtering AF 0.00143% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000894%

Overall 0.000959% 14/1,460,364 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00441%	22,668
Remaining individualsnot grpmax-eligible	0.0016%	62,420
European (non-Finnish)	0.000763%	131,059

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: EMC3
Protein: p.Arg93Trp
Coding: c.277C>T
MANE Select: NM_001394674
Type: single nucleotide variant
Location: chr3:9976987 (GRCh38)
Gene constraint: LOEUF 0.548 · pLI 0.92 (gnomAD)
Structure: AlphaFold pLDDT 78.38 · 10 PDB

Full EMC3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

EMC3 c.-242+3401G>A Uncertain significance ★ same type
EMC3 c.-242+3659C>G Uncertain significance ★ same type
EMC3 p.Ala212Thr Uncertain significance ★ ⚠ same type
EMC3 p.Arg180Trp Uncertain significance ★ ⚠ same type
EMC3 p.Arg57Gln Uncertain significance ★ ⚠ same type
EMC3 p.Asn175Ser Uncertain significance ★ ⚠ same type
EMC3 p.Asp41Asn Uncertain significance ★ ⚠ same type
EMC3 p.Asp41His Uncertain significance ★ ⚠ same type

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/emc3-p-arg93trp (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown